Asthma is a common chronic disease worldwide and affects approximately 24 million persons in

the United States. It is the most common chronic disease in childhood, affecting an estimated 7
million children. The pathophysiology of asthma is complex and involves airway inflammation,
intermittent airflow obstruction, and bronchial hyperresponsiveness. See the image below.
Pathogenesis of asthma. Antigen presentation by the dendritic cell with the lymphocyte and
cytokine response leading to airway inflammation and asthma symptoms.

Essential update: Studies show that mepolizumab relieves severe asthma

In a pair of recent studies, treatment with the monoclonal antibody mepolizumab, administered
subcutaneously, improved disease control and reduced exacerbations in patients with severe
eosinophilic asthma.[1]
In the first study, the Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma
(MENSA) trial, 576 patients were randomized to treatment with 75 mg of intravenous
mepolizumab, 100 mg of subcutaneous mepolizumab, or placebo every 4 weeks for 32 weeks.
Compared with patients who received placebo, the rate of exacerbations was reduced by 47%
among patients who received intravenous mepolizumab and by 53% among patients who
received subcutaneous mepolizumab (P< 0.001 for both comparisons).[2]
In the second study, the Steroid Reduction with Mepolizumab Study (SIRIUS), patients were
treated with a subcutaneous 100-mg dose of mepolizumab or placebo every 4 weeks for 20
weeks. Patients in the mepolizumab group had significant decreases in oral glucocorticoid
steroid dependence compared with those in the placebo group placebo (odds ratio, 2.39; 95%
confidence interval, 1.25 - 4.56; P = .008). Median percentage reduction from baseline in
glucocorticoid dose was 50% with mepolizumab treatment, compared with no reduction with
placebo (P = .007).[3]

Signs and symptoms

Signs and symptoms of asthma include the following:

Wheezing
Coughing

Shortness of breath

Chest tightness/pain

Other nonspecific symptoms in infants or young children may be a history of recurrent

bronchitis, bronchiolitis, or pneumonia; a persistent cough with colds; and/or recurrent croup or
chest rattling.
See Clinical Presentation for more detail.

Diagnosis
Updated guidelines from the National Asthma Education and Prevention Program highlight the
importance of correctly diagnosing asthma, by establishing the following[4] :

Episodic symptoms of airflow obstruction are present

Airflow obstruction or symptoms are at least partially reversible

Exclusion of alternative diagnoses

Spirometry with postbronchodilator response should be obtained as the primary test to establish
the asthma diagnosis. Pulse oximetry measurement is desirable in all patients with acute asthma
to exclude hypoxemia. The chest radiograph remains the initial imaging evaluation in most
individuals with symptoms of asthma, but in most patients with asthma, chest radiography
findings are normal or may indicate hyperinflation. Exercise spirometry is the standard method
for assessing patients with exercise-induced bronchospasm.
See Workup for more detail.

Management
For all but the most severely affected patients, the ultimate goal is to prevent symptoms,
minimize morbidity from acute episodes, and prevent functional and psychological morbidity to
provide a healthy (or near healthy) lifestyle appropriate to the age of child.
Pharmacologic treatment
Pharmacologic management includes the use of relief and control agents. Control agents include
inhaled corticosteroids, inhaled cromolyn (Intal) or nedocromil (Tilade), long-acting
bronchodilators, theophylline (Theo-24, Theochron, Uniphyl), leukotriene modifiers, and antiIgE antibodies. Relief medications include short-acting bronchodilators, systemic corticosteroids,
and ipratropium (Atrovent).

The pharmacologic treatment of asthma is based on stepwise therapy. Asthma medications

should be added or deleted as the frequency and severity of the patient's symptoms change.
Allergen avoidance
Environmental exposures and irritants can play a strong role in symptom exacerbations. The use
of skin testing or in vitro testing to assess sensitivity to perennial indoor allergens is important.
Once the offending allergens are identified, counsel patients on how to avoid them. Efforts
should focus on the home, where specific triggers include dust mites, animals, cockroaches,
mold, and pollen.

Background
Asthma is a common chronic disease worldwide and affects approximately 24 million persons in
the United States. It is the most common chronic disease in childhood, affecting an estimated 7
million children, and it is a common cause of hospitalization for children in the United States.
The pathophysiology of asthma is complex and involves airway inflammation, intermittent
airflow obstruction, and bronchial hyperresponsiveness. The mechanism of inflammation in
asthma may be acute, subacute, or chronic, and the presence of airway edema and mucus
secretion also contributes to airflow obstruction and bronchial reactivity. Varying degrees of
mononuclear cell and eosinophil infiltration, mucus hypersecretion, desquamation of the
epithelium, smooth muscle hyperplasia, and airway remodeling are present.[5, 6]
Airway hyperresponsiveness or bronchial hyperreactivity in asthma is an exaggerated response
to numerous exogenous and endogenous stimuli. The mechanisms involved include direct
stimulation of airway smooth muscle and indirect stimulation by pharmacologically active
substances from mediator-secreting cells such as mast cells or nonmyelinated sensory neurons.
The degree of airway hyperresponsiveness generally correlates with the clinical severity of
asthma.
Spirometry with postbronchodilator response should be obtained as the primary test to establish
the asthma diagnosis. Pulse oximetry measurement is desirable in all patients with acute asthma
to exclude hypoxemia. The chest radiograph remains the initial imaging evaluation in most
individuals with symptoms of asthma, but in most patients with asthma, chest radiography
findings are normal or may indicate hyperinflation. Exercise spirometry is the standard method
for assessing patients with exercise-induced bronchospasm.
Physical findings vary with the severity of the asthma and with the absence or presence of an
acute episode and its severity. The severity of asthma is classified as intermittent, mild persistent,
moderate persistent, or severe persistent. Patients with asthma of any level of severity may have
mild, moderate, or severe exacerbations.
Pharmacologic management includes the use of relief and control agents. Control agents include
inhaled corticosteroids, inhaled cromolyn (Intal) or nedocromil (Tilade), long-acting
bronchodilators, theophylline (Theo-24, Theochron, Uniphyl), leukotriene modifiers, and anti-

IgE antibodies. Relief medications include short-acting bronchodilators, systemic corticosteroids,

and ipratropium (Atrovent). With severe exacerbations, indications for hospitalization are based
on findings after the patient receives 3 doses of an inhaled bronchodilator. In general, patients
should be assessed every 1-6 months for asthma control.

Anatomy
The airways of the lungs consist of the cartilaginous bronchi, membranous bronchi, and gasexchanging bronchi termed the respiratory bronchioles and alveolar ducts. While the first 2 types
function mostly as anatomic dead space, they also contribute to airway resistance. The smallest
non-gas-exchanging airways, the terminal bronchioles, are approximately 0.5 mm in diameter;
airways are considered small if they are less than 2 mm in diameter.[7]
Airway structure consists of the following:

Mucosa, which is composed of epithelial cells that are capable of specialized

mucous production and a transport apparatus
Basement membrane

A smooth-muscle matrix extending to the alveolar entrances

Predominantly fibrocartilaginous or fibroelastic-supporting connective tissue.

Cellular elements include mast cells, which are involved in the complex control of releasing
histamine and other mediators. Basophils, eosinophils, neutrophils, and macrophages also are
responsible for extensive mediator release in the early and late stages of bronchial asthma.
Stretch and irritant receptors reside in the airways, as do cholinergic motor nerves, which
innervate the smooth muscle and glandular units. In bronchial asthma, smooth muscle
contraction in an airway is greater than that expected for its size if it were functioning normally,
and this contraction varies in its distribution.

Pathophysiology
The 2007 Expert Panel Report 3 (EPR-3) of the National Asthma Education and Prevention
Program (NAEPP) noted several key changes in the understanding of the pathophysiology of
asthma[8] :

The critical role of inflammation has been further substantiated, but evidence
is emerging for considerable variability in the pattern of inflammation, thus
indicating phenotypic differences that may influence treatment responses
Of the environmental factors, allergic reactions remain important. Evidence
also suggests a key and expanding role for viral respiratory infections in
these processes
The onset of asthma for most patients begins early in life, with the pattern of
disease persistence determined by early, recognizable risk factors including
atopic disease, recurrent wheezing, and a parental history of asthma

Current asthma treatment with anti-inflammatory therapy does not appear to

prevent progression of the underlying disease severity

The pathophysiology of asthma is complex and involves the following components:

Airway inflammation
Intermittent airflow obstruction

Bronchial hyperresponsiveness

Airway inflammation
The mechanism of inflammation in asthma may be acute, subacute, or chronic, and the presence
of airway edema and mucus secretion also contributes to airflow obstruction and bronchial
reactivity. Varying degrees of mononuclear cell and eosinophil infiltration, mucus
hypersecretion, desquamation of the epithelium, smooth muscle hyperplasia, and airway
remodeling are present.[5] See the image below.

Pathogenesis of asthma. Antigen presentation by the

dendritic cell with the lymphocyte and cytokine response leading to airway
inflammation and asthma symptoms.

Some of the principal cells identified in airway inflammation include mast cells, eosinophils,
epithelial cells, macrophages, and activated T lymphocytes. T lymphocytes play an important
role in the regulation of airway inflammation through the release of numerous cytokines. Other
constituent airway cells, such as fibroblasts, endothelial cells, and epithelial cells, contribute to
the chronicity of the disease. Other factors, such as adhesion molecules (eg, selectins, integrins),
are critical in directing the inflammatory changes in the airway. Finally, cell-derived mediators
influence smooth muscle tone and produce structural changes and remodeling of the airway.
The presence of airway hyperresponsiveness or bronchial hyperreactivity in asthma is an
exaggerated response to numerous exogenous and endogenous stimuli. The mechanisms
involved include direct stimulation of airway smooth muscle and indirect stimulation by
pharmacologically active substances from mediator-secreting cells such as mast cells or
nonmyelinated sensory neurons. The degree of airway hyperresponsiveness generally correlates
with the clinical severity of asthma.

A study by Balzar et al reported changes in airway resident mast cell populations from a large
group of subjects with asthma and normal control subjects.[9] A greater proportion of chymasepositive mast cells in the airways and increased prostaglandin D2 levels were identified as
important predictors of severe asthma as compared with other steroid-treated subjects with
asthma.
Chronic inflammation of the airways is associated with increased bronchial hyperresponsiveness,
which leads to bronchospasm and typical symptoms of wheezing, shortness of breath, and
coughing after exposure to allergens, environmental irritants, viruses, cold air, or exercise. In
some patients with chronic asthma, airflow limitation may be only partially reversible because of
airway remodeling (hypertrophy and hyperplasia of smooth muscle, angiogenesis, and
subepithelial fibrosis) that occurs with chronic untreated disease.
Airway inflammation in asthma may represent a loss of normal balance between two "opposing"
populations of Th lymphocytes. Two types of Th lymphocytes have been characterized: Th1 and
Th2. Th1 cells produce interleukin (IL)-2 and IFN-, which are critical in cellular defense
mechanisms in response to infection. Th2, in contrast, generates a family of cytokines (IL-4, IL5, IL-6, IL-9, and IL-13) that can mediate allergic inflammation. A study by Gauvreau et al found
that IL-13 has a role in allergen-induced airway responses.[10]
The current "hygiene hypothesis" of asthma illustrates how this cytokine imbalance may explain
some of the dramatic increases in asthma prevalence in westernized countries.[11] This hypothesis
is based on the concept that the immune system of the newborn is skewed toward Th2 cytokine
generation (mediators of allergic inflammation). Following birth, environmental stimuli such as
infections activate Th1 responses and bring the Th1/Th2 relationship to an appropriate balance.

Airflow obstruction
Airflow obstruction can be caused by a variety of changes, including acute bronchoconstriction,
airway edema, chronic mucous plug formation, and airway remodeling. Acute
bronchoconstriction is the consequence of immunoglobulin E-dependent mediator release upon
exposure to aeroallergens and is the primary component of the early asthmatic response. Airway
edema occurs 6-24 hours following an allergen challenge and is referred to as the late asthmatic
response. Chronic mucous plug formation consists of an exudate of serum proteins and cell
debris that may take weeks to resolve. Airway remodeling is associated with structural changes
due to long-standing inflammation and may profoundly affect the extent of reversibility of
airway obstruction.[12]
Airway obstruction causes increased resistance to airflow and decreased expiratory flow rates.
These changes lead to a decreased ability to expel air and may result in hyperinflation. The
resulting overdistention helps maintain airway patency, thereby improving expiratory flow;
however, it also alters pulmonary mechanics and increases the work of breathing.

Bronchial hyperresponsiveness

Hyperinflation compensates for the airflow obstruction, but this compensation is limited when
the tidal volume approaches the volume of the pulmonary dead space; the result is alveolar
hypoventilation. Uneven changes in airflow resistance, the resulting uneven distribution of air,
and alterations in circulation from increased intra-alveolar pressure due to hyperinflation all lead
to ventilation-perfusion mismatch. Vasoconstriction due to alveolar hypoxia also contributes to
this mismatch. Vasoconstriction is also considered an adaptive response to ventilation/perfusion
mismatch.
In the early stages, when ventilation-perfusion mismatch results in hypoxia, hypercarbia is
prevented by the ready diffusion of carbon dioxide across alveolar capillary membranes. Thus,
patients with asthma who are in the early stages of an acute episode have hypoxemia in the
absence of carbon dioxide retention. Hyperventilation triggered by the hypoxic drive also causes
a decrease in PaCO2. An increase in alveolar ventilation in the early stages of an acute
exacerbation prevents hypercarbia. With worsening obstruction and increasing ventilationperfusion mismatch, carbon dioxide retention occurs. In the early stages of an acute episode,
respiratory alkalosis results from hyperventilation. Later, the increased work of breathing,
increased oxygen consumption, and increased cardiac output result in metabolic acidosis.
Respiratory failure leads to respiratory acidosis.

Etiology
Factors that can contribute to asthma or airway hyperreactivity may include any of the following:

Environmental allergens (eg, house dust mites; animal allergens, especially

cat and dog; cockroach allergens; and fungi)
Viral respiratory tract infections

Exercise, hyperventilation

Gastroesophageal reflux disease

Chronic sinusitis or rhinitis

Aspirin or nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity,

sulfite sensitivity

Use of beta-adrenergic receptor blockers (including ophthalmic preparations)

Obesity

Environmental pollutants, tobacco smoke

Occupational exposure

Irritants (eg, household sprays, paint fumes)

Various high- and low-molecular-weight compounds (eg, insects, plants, latex,

gums, diisocyanates, anhydrides, wood dust, and fluxes; associated with
occupational asthma)

[13]

Emotional factors or stress

Perinatal factors (prematurity and increased maternal age; maternal smoking

and prenatal exposure to tobacco smoke; breastfeeding has not been
definitely shown to be protective)

Aspirin-induced asthma
The triad of asthma, aspirin sensitivity, and nasal polyps affects 5-10% of patients with asthma.
Most patients experience symptoms during the third to fourth decade. A single dose can provoke
an acute asthma exacerbation, accompanied by rhinorrhea, conjunctival irritation, and flushing of
the head and neck. It can also occur with other nonsteroidal anti-inflammatory drugs and is
caused by an increase in eosinophils and cysteinyl leukotrienes after exposure.[14]
A study by Beasley et al demonstrated some epidemiological evidence that exposure to
acetaminophen is associated with an increased risk of asthma.[15] However, no clinical studies
have directly linked asthma symptoms with acetaminophen use.
Primary treatment is avoidance of these medications, but leukotriene antagonists have shown
promise in treatment, allowing these patients to take daily aspirin for cardiac or rheumatic
disease.

Gastroesophageal reflux disease

The presence of acid in the distal esophagus, mediated via vagal or other neural reflexes, can
significantly increase airway resistance and airway reactivity. Patients with asthma are 3 times
more likely to also have GERD.[16] Some people with asthma have significant gastroesophageal
reflux without esophageal symptoms. Gastroesophageal reflux was found to be a definite
asthma-causing factor (defined by a favorable asthma response to medical antireflux therapy) in
64% of patients; clinically silent reflux was present in 24% of all patients.[16]

Work-related asthma
Occupational factors are associated with 10-15% of adult asthma cases. More than 300 specific
occupational agents have been associated with asthma. High-risk jobs include farming, painting,
janitorial work, and plastics manufacturing. Given the prevalence of work-related asthma, the
American College of Chest Physicians (ACCP) supports consideration of work-related asthma in
all patients presenting with new-onset or worsening asthma. An ACCP consensus statement
defines work-related asthmas as including occupational asthma (ie, asthma induced by sensitizer
or irritant work exposures) and work-exacerbated asthma (ie, preexisting or concurrent asthma
worsened by work factors).[17]
Two types of occupational asthma are recognized: immune-related and non-immune-related.
Immune-mediated asthma has a latency of months to years after exposure. Non-immunemediated asthma, or irritant-induced asthma (reactive airway dysfunction syndrome), has no
latency period and may occur within 24 hours after an accidental exposure to high concentrations

of respiratory irritants. Pay careful attention to the patient's occupational history. Those with a
history of asthma who report worsening of symptoms during the week and improvement during
the weekends should be evaluated for occupational exposure. Peak-flow monitoring during work
(optimally, at least 4 times a day) for at least 2 weeks and a similar period away from work is one
recommended method to establish the diagnosis.[17]
To see complete information on Allergic and Environmental Asthma, please go to the main
article by clicking here.

Viral exposure in children

Evidence suggests that rhinovirus illness during infancy is a significant risk factor for the
development of wheezing in preschool children and a frequent trigger of wheezing illnesses in
children with asthma.[18] Human rhinovirus C (HRVC) is a newly identified genotype of HRV
found in patients with respiratory tract infections. A study of children with acute asthma who
presented to the emergency department found HRVC present in the majority of patients. The
presence of HRVC was also associated with more severe asthma.[19]
Approximately 80-85% of childhood asthma episodes are associated with prior viral exposure.
Prior childhood pneumonia due to infection by respiratory syncytial virus, Mycoplasma
pneumoniae, and/or Chlamydia species was found in more than 50% of a small sample of
children aged 7-9 years who later had asthma.[20] Treatment with antibiotics appropriate for these
organisms improves the clinical signs and symptoms of asthma.

Sinusitis
Of patients with asthma, 50% have concurrent sinus disease. Sinusitis is the most important
exacerbating factor for asthma symptoms. Either acute infectious sinus disease or chronic
inflammation may contribute to worsening airway symptoms. Treatment of nasal and sinus
inflammation reduces airway reactivity. Treatment of acute sinusitis requires at least 10 days of
antibiotics to improve asthma symptoms.[21]

Exercise-induced asthma
Exercise-induced asthma (EIA), or exercise-induced bronchospasm (EIB), is an asthma variant
defined as a condition in which exercise or vigorous physical activity triggers acute
bronchospasm in persons with heightened airway reactivity. It is observed primarily in persons
who have asthma (exercise-induced bronchospasm in asthmatic persons) but can also be found in
patients with normal resting spirometry findings with atopy, allergic rhinitis, or cystic fibrosis
and even in healthy persons, many of whom are elite athletes (exercise-induced bronchospasm in
athletes). Exercise-induced bronchospasm is often a neglected diagnosis, and the underlying
asthma may be silent in as many as 50% of patients, except during exercise.[22, 23]
The pathogenesis of exercise-induced bronchospasm is controversial. The disease may be
mediated by water loss from the airway, heat loss from the airway, or a combination of both. The
upper airway is designed to keep inspired air at 100% humidity and body temperature at 37C

(98.6F). The nose is unable to condition the increased amount of air required for exercise,
particularly in athletes who breathe through their mouths. The abnormal heat and water fluxes in
the bronchial tree result in bronchoconstriction, occurring within minutes of completing exercise.
Results from bronchoalveolar lavage studies have not demonstrated an increase in inflammatory
mediators. These patients generally develop a refractory period, during which a second exercise
challenge does not cause a significant degree of bronchoconstriction.
Factors that contribute to exercise-induced bronchospasm symptoms (in both people with asthma
and athletes) include the following:

Exposure to cold or dry air

Environmental pollutants (eg, sulfur, ozone)

level of bronchial hyperreactivity

Chronicity of asthma and symptomatic control

Duration and intensity of exercise

Allergen exposure in atopic individuals

Coexisting respiratory infection

The assessment and diagnosis of exercise-induced bronchospasm is made more often in children
and young adults than in older adults and is related to high levels of physical activity. Exerciseinduced bronchospasm can be observed in persons of any age based on the level of underlying
airway reactivity and the level of physical exertion.

Genetics
Research on genetic mutations casts further light on the synergistic nature of multiple mutations
in the pathophysiology of asthma. Polymorphisms in the gene that encodes platelet-activating
factor hydrolase, an intrinsic neutralizing agent of platelet-activating factor in most humans, may
play a role in susceptibility to asthma and asthma severity.[24]
Evidence suggests that the prevalence of asthma is reduced in association with certain infections
(Mycobacterium tuberculosis, measles, or hepatitis A); rural living; exposure to other children
(eg, presence of older siblings and early enrollment in childcare); and less frequent use of
antibiotics. Furthermore, the absence of these lifestyle events is associated with the persistence
of a Th2 cytokine pattern. Under these conditions, the genetic background of the child, with a
cytokine imbalance toward Th2, sets the stage to promote the production of immunoglobulin E
(IgE) antibody to key environmental antigens (eg, dust mites, cockroaches, Alternaria, and
possibly cats). Therefore, a gene-by-environment interaction occurs in which the susceptible host
is exposed to environmental factors that are capable of generating IgE, and sensitization occurs.
A reciprocal interaction is apparent between the 2 subpopulations, in which Th1 cytokines can
inhibit Th2 generation and vice versa. Allergic inflammation may be the result of an excessive
expression of Th2 cytokines. Alternatively, recent studies suggest the possibility that the loss of

normal immune balance arises from a cytokine dysregulation in which Th1 activity in asthma is
diminished.[25]
In addition, some studies highlight the importance of genotypes in children's susceptibility to
asthma and response to specific antiasthma medications.[26, 27, 28, 29]

Obesity
A study by Cottrell et al explored the relationship between asthma, obesity, and abnormal lipid
and glucose metabolism.[30] The study found that community-based data linked asthma, body
mass, and metabolic variables in children. Specifically, these findings described a statistically
significant association between asthma and abnormal lipid and glucose metabolism beyond body
mass association.
Accelerated weight gain in early infancy is associated with increased risks of asthma symptoms
according to one study of preschool children.[31]
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